Acquired peripheral neuropathy commonly results from diabetes, chemotherapy and HIV/AIDS, and therefore imposes a considerable, and increasing, health care burden on society. Effective treatment of neuropathy requires an understanding of the interactions between glia and axons in the peripheral nerve. Myelinating Schwann cells have been studied extensively, but less is known about non-myelinating Schwann cells. Because they are associated with unmyelinated sensory fibers that transmit pain, they are likely to participate in the pathology associated with diabetic and other small-fibe neuropathies. Furthermore, Schwann cell-specific mutations in genes that are important for cellular metabolism strongly affect unmyelinated axon stability, revealing an important but little explored link between these cells and peripheral nerve disease. Therefore an understanding of the biology of non-myelinating Schwann cells is an important approach toward developing new treatments for peripheral nerve diseases. We have developed several independent approaches for obtaining gene expression profiles of non-myelinating Schwann cells in order to identify new markers for these cells, and to identify mechanisms whereby their functional impairment in disease, particularly metabolic disease, affects peripheral nerve function. In addition, we have generated transgenic mice that express two proteins, an eGFP-tagged ribosomal protein, and tamoxifen-inducible Cre recombinase, in non-myelinating Schwann cells. The tagged ribosomal protein will permit the isolation and profiling of polyribosome-associated mRNAs in non-myelinating Schwann cells by translating ribosome affinity purification, or TRAP, a powerful method for determining gene expression profiles of specific cell types. The Cre recombinase will permit us to specifically manipulate gene expression in non-myelinating Schwann cells, or ablate them entirely. Such experiments are necessary to dissect the complex interactions between non-myelinating Schwann cells and their associated axons. These new transgenic mouse lines will permit us to establish gene expression signatures of non-myelinating Schwann cells after genetic or environmental perturbation and in models of inherited or acquired PNS disease. In particular we will use these methods to investigate the molecular aspects of how metabolic deficits lead to unmyelinated axon loss and neuropathy. Through the identification and manipulation of genes altered in non-myelinating Schwann cells in health and disease, we hope to gain new insights into the underlying pathology and open up new avenues for treatment of peripheral neuropathies.